Mitochondrial proton leak and neonatal brain injury

线粒体质子泄漏与新生儿脑损伤

• 批准号: 10724518
• 负责人: Alexander Galkin
• 金额: $ 64.98万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-19 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10724518
• 关键词: ATP phosphohydrolase; Ablation; Acids; Address; Adenine Nucleotides; Adult; Affect; Attenuated; Automobile Driving; Bioenergetics; Biological Assay; Biophysical Process; Biophysics; Brain; Brain Hypoxia-Ischemia; Brain Injuries; Brain Ischemia; Buffers; Cell Death; Cells; Cessation of life; Child; Clinical; Complex; Confusion; Cyclosporine; Disease; Event; Failure; Genetic; Hour; Hypoxic-Ischemic Brain Injury; Injury; Inner mitochondrial membrane; Ions; Ischemic Brain Injury; Mitochondria; Mitochondrial Proteins; Modeling; Modification; Mus; NADH; Neonatal; Neonatal Brain Injury; Neurologic Deficit; Pathogenicity; Perinatal Hypoxia; Permeability; Production; Property; Proton-Motive Force; Protons; Rattus; Recovery; Regulation; Reperfusion Therapy; Reporting; Reproducibility; Research; Respiration; Respiratory Chain; Role; SLC25A4 gene; Secondary to; Severities; Specific qualifier value; Stress; Structure; Structure-Activity Relationship; Testing; Therapeutic; Time; Work; cell injury; cyclophilin D; deprivation; disability; effective therapy; improved; inhibitor; mature animal; mitochondrial dysfunction; mitochondrial membrane; mitochondrial permeability transition pore; natural hypothermia; neonatal brain; neonatal hypoxic-ischemic brain injury; neonatal mice; neonate; neuroprotection; new therapeutic target; newborn brain injury; novel; patch clamp; pharmacologic; preservation; prevent; reconstitution; response

SUMMARY Neonatal brain injuries, hypoxia-ischemia (HI) brain injury is one of the leading causes of disability in children. Mitochondrial dysfunction due to activation of permeability transition pore (mPTP) has been implicated in cell death after HI insult but only in the mature brain. It has been proposed that mPTP is non-specific protons/ions leak across the inner mitochondrial membrane which dissipates proton motive force and renders mitochondria deficient or incapable of ATP production, often driving cellular death in the ischemic brain. However, the strategies to address mPTP in the model of HI brain injury in neonatal mice or rats were unsuccesful. Thus, an identical biophysical process, an activation of mPTP, triggered by similar HI stress contributes to the brain injury in the mature animals and may not be mechanistically significant in the immature brain. We have reasoned and found that biophysical and pharmacological properties of the mPTP activated during HI in neonates differ from that in adult animals. In neonates these mPTP are not cyclophilin D (CypD) dependent. This a) defines neonatal failure of the strategies which are neuroprotective in adults and b) require a different therapeutic approach. Aim 1. To determine if CypD-independent mML contributes to SEF and cellular injury during reperfusion. Aim 2. To determine the pharmacological regulation and structure of CypD- independent mitochondrial membrane leaks. Aim 3. To determine the role of CypD-dependent mPT in neonatal HI brain injury. Our work will provide the very first direct evidence for pathogenic role of mitochondrial permeabilization in neonatal HI brain injury models. This will allow us to better understand its regulation and structure function relationship and help to develop highly efficient strategies of brain protection against hypoxic ischemic stress by direct targeting of the ion-conducting parts of the mPTP.

摘要 新生儿脑损伤、缺氧缺血性脑损伤是我国新生儿致残的主要原因之一。 孩子们。线粒体功能障碍与通透性转换孔(MPTP)的激活有关 在HI后的细胞死亡中，但仅在成熟的大脑中。有人提出MPTP是非特定的 质子/离子泄漏穿过线粒体内膜，从而消散质子动力并使 线粒体缺乏或不能产生三磷酸腺苷，通常导致脑缺血时的细胞死亡。 然而，在新生小鼠或大鼠缺氧缺血性脑损伤模型中处理MPTP的策略是 不成功。因此，一个相同的生物物理过程，即MPTP的激活，由类似的HI应激触发 在成熟动物中对脑损伤有贡献，而在未成熟动物中可能不具有机械意义 大脑。我们推测并发现MPTP的生物物理和药理性质被激活 在HI期间，新生儿不同于成年动物。在新生儿中，这些MPTP不是亲环素D(CypD) 依附的。这a)定义了对成人具有神经保护作用的新生儿衰竭的策略，以及b)要求 一种不同的治疗方法。目的1.确定CypD非依赖性MML是否对SEF和细胞有贡献 再灌注期损伤。目的2.确定CypD-2的药理调节和结构。 独立的线粒体膜渗漏。目的3.确定CypD依赖的MPT在新生儿中的作用 嗨，脑部受伤。 我们的工作将为线粒体通透性的致病作用提供第一个直接证据。 新生大鼠缺氧缺血性脑损伤模型。这将使我们更好地了解它的调节和结构功能 发展高效的脑保护策略对抗缺氧缺血性应激的关系和帮助 通过直接靶向MPTP的离子传导部分。